WO2011126089A1 - 体液由来検体を用いた横紋筋肉腫の検出方法 - Google Patents

体液由来検体を用いた横紋筋肉腫の検出方法 Download PDF

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WO2011126089A1
WO2011126089A1 PCT/JP2011/058843 JP2011058843W WO2011126089A1 WO 2011126089 A1 WO2011126089 A1 WO 2011126089A1 JP 2011058843 W JP2011058843 W JP 2011058843W WO 2011126089 A1 WO2011126089 A1 WO 2011126089A1
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mir
hsa
rhabdomyosarcoma
expression
mirna
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PCT/JP2011/058843
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English (en)
French (fr)
Japanese (ja)
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創 細井
充 宮地
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京都府公立大学法人
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Priority to JP2012509705A priority Critical patent/JP5928725B2/ja
Priority to US13/639,183 priority patent/US8975021B2/en
Priority to CA2795430A priority patent/CA2795430A1/en
Priority to CN201180028448.9A priority patent/CN103108953B/zh
Priority to EP11765989.6A priority patent/EP2557162B1/en
Priority to ES11765989.6T priority patent/ES2549452T3/es
Priority to KR1020127027613A priority patent/KR20130069587A/ko
Publication of WO2011126089A1 publication Critical patent/WO2011126089A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA

Definitions

  • the present invention relates to a method for detecting rhabdomyosarcoma using a body fluid-derived specimen.
  • Non-Patent Documents 1 and 2 The inventors of the present invention have been working on the development of a noninvasive diagnostic technique using a tumor-derived free DNA in serum (Non-Patent Documents 1 and 2).
  • the presence of non-coding RNA that is not translated into a protein called microRNA (miRNA) has been clarified, and its expression profile has been reported to be tissue or tumor specific (Non-Patent Documents 3 and 4).
  • Non-patent Document 5 Even in childhood cancer, there is a report that the expression profile differs depending on the tumor in studies using cell lines.
  • Non-patent Documents 5 and 6 the expression of miRNA specifically expressed in muscle is increased.
  • tumor-derived miRNA exists in serum, suggesting the usefulness of miRNA as a biomarker in colorectal cancer, lymphoma, prostate cancer, liver cancer, etc. (non-patented) References 7-10).
  • the present invention aims to provide a method for easily detecting rhabdomyosarcoma that is difficult to diagnose.
  • the present inventors quantified hsa-miR-1, 133a, 133b, and 206, a miRNA group specifically expressed in muscle, in a sample derived from a body fluid of a pediatric tumor patient, and non-invasively rhabdomyosarcoma We examined whether diagnosis was possible. As a result, it was found that rhabdomyosarcoma can be detected by these miRNAs.
  • the present invention provides the following method for detecting rhabdomyosarcoma.
  • Item 1. Characterized in that the expression of at least one miRNA selected from the group consisting of hsa-miR-1, hsa-miR-133a, hsa-miR-133b and hsa-miR-206 is evaluated in a sample derived from a body fluid , Detection method of rhabdomyosarcoma.
  • Item 2 Characterized in that the expression of at least one miRNA selected from the group consisting of hsa-miR-1, hsa-miR-133a, hsa-miR-133b and hsa-miR-206 is evaluated in a sample derived from a body fluid , Detection method of rhabdomyosarcoma.
  • the expression level of at least one selected from the group consisting of hsa-miR-1, hsa-miR-133a, hsa-miR-133b, and hsa-miR-206 is significantly increased from that of healthy subjects Item 2.
  • Item 3. The method for detecting rhabdomyosarcoma according to Item 1, wherein the expression of at least one miRNA selected from the group consisting of hsa-miR-133a, hsa-miR-133b and hsa-miR-206 is evaluated.
  • Item 4. Item 2. The method for detecting rhabdomyosarcoma according to Item 1, wherein the expression of at least hsa-miR-206 is evaluated.
  • Item 5. Item 2. The method for detecting rhabdomyosarcoma according to Item 1, which is detected by a real-time PCR method.
  • Item 6. Item 2. The method for detecting rhabdomyosarcoma according to Item 1, wherein the body fluid is blood and the sample derived from the body fluid is plasma or serum.
  • Rhabdomyosarcoma is one of the tumors that are difficult to diagnose, but according to the present invention, rhabdomyosarcoma can be detected using a sample derived from a body fluid that has been considered impossible. .
  • rhabdomyosarcoma For rhabdomyosarcoma, it is important to improve the prognosis by completely removing the tumor before chemotherapy and radiation therapy, and it is possible to make a provisional diagnosis before surgery and determine the surgical strategy with the goal of complete removal at the first time. is important. According to the present invention, rhabdomyosarcoma can be diagnosed more accurately and quickly, and improvement in treatment results for rhabdomyosarcoma can be expected.
  • the rhabdomyosarcoma cell line shows enhanced expression of muscle-specific microRNA.
  • the vertical axis represents the ratio between muscle-specific miRNA and hsa-miR-16.
  • RMS rhabdomyosarcoma
  • NB neuroblastoma
  • EWS Ewing sarcoma
  • MRT malignant rhabdomyosarcoma.
  • the vertical axis represents the ratio between muscle-specific miRNA and hsa-miR-16.
  • RMS Nonrhabdomyosarcoma
  • nonRMS ⁇ ⁇ Tumors other than rhabdomyosarcoma.
  • the expression level of the culture supernatant of the rhabdomyosarcoma cell lines of hsa-miR-1, hsa-miR-206, hsa-miR-133a, and hsa-miR-133b is shown.
  • the vertical axis represents the ratio between muscle-specific miRNA and hsa-miR-16.
  • RMS Rhabdomyosarcoma
  • NB Neuroblastoma
  • EWS Ewing sarcoma
  • MRT Malignant rhabdomyosarcoma.
  • the vertical axis represents the hsa-miR-1 / hsa-miR-16 ratio.
  • RMS Nonrhabdomyosarcoma, nonRMS ⁇ ⁇ : Tumors other than rhabdomyosarcoma.
  • the vertical axis represents the hsa-miR-133a / hsa-miR-16 ratio.
  • RMS Nonrhabdomyosarcoma, nonRMS ⁇ ⁇ : Tumors other than rhabdomyosarcoma.
  • the vertical axis represents the hsa-miR-133b / hsa-miR-16 ratio.
  • RMS Nonrhabdomyosarcoma
  • nonRMS ⁇ ⁇ Tumors other than rhabdomyosarcoma.
  • the vertical axis represents the hsa-miR-206 / hsa-miR-16 ratio.
  • RMS Nonrhabdomyosarcoma
  • nonRMS ⁇ ⁇ Tumors other than rhabdomyosarcoma.
  • the vertical axis represents the muscle-specific miRNA / hsa-miR-16 ratio.
  • Stability of miRNA in human serum The stability of serum microRNA was verified by storage at 4 ° C. Ct values in both hsa-miR-16 and hsa-miR-133b tended to increase gradually with the storage period, and increased 3 to 4 on day 30 (1/16 to 1/8 as an absolute amount).
  • Serum muscle-specific miRNA is shown to reflect the pathology of rhabdomyosarcoma. It shows that muscle-specific miRNA is also detected in body fluids (spinal fluid, pleural effusion) other than serum of children with rhabdomyosarcoma. It shows that muscle-specific miRNA in body fluids reflects the pathology of rhabdomyosarcoma.
  • Table 1 shows the sequence of hsa-miR-16 that can be used as an internal control because of its high expression and less variation in expression between tissues.
  • hsa-miR-1, hsa-miR-133a, hsa-miR-133b and hsa-miR-206 are released in large amounts in the culture supernatant of rhabdomyosarcoma cell line, as shown in FIG.
  • Tumor-derived miRNA exists free from tumor cells. Even in the human body, it can be used for detection and diagnosis of rhabdomyosarcoma due to the presence of free miRNA derived from tumors in body fluids.
  • examples of the body fluid include blood, pleural effusion, ascites, cerebrospinal fluid, and urine.
  • Blood is effective regardless of the site of rhabdomyosarcoma or the site of metastasis, but urine is generated when the site of occurrence or metastasis is the urinary organ, cerebrospinal fluid is used in the central nervous system, etc.
  • ascites is effective, and in the case of thoracic cavity, pleural effusion is effective.
  • the miRNA used in the present invention can be detected from a serum sample stored at -20 ° C. 20 years ago, and has sufficient stability in serum for use in the present invention (FIG. 9). For example, when serum is stored at 4 ° C. for 30 days, the absolute amount is about 1/16 to 1/8, but the ratio of hsa-miR-133b and hsa-miR-16 did not change significantly.
  • Detecting and quantifying miRNA can be performed by reverse transcription of a sample containing miRNA to obtain cDNA, and this can be performed by an appropriate method such as quantitative real-time PCR.
  • cDNA can be prepared by performing a reverse transcription reaction using, for example, TaqMan MicroRNA RT kit (Applied Biosystems), TaqMan MicroRNA assays Mature microRNA-specific RT primer.
  • Quantitative real-time PCR can be performed using TaqMan RNA assays Taqman primer and probe, TaqMan Universal PCR Master Mix.
  • the expression of muscle-specific miRNA is significantly increased in the rhabdomyosarcoma group at p ⁇ 0.05.
  • Hsa-miR-206 has the highest sensitivity and specificity and is considered useful as the miRNA to be measured. For hsa-miR-133a, hsa-miR-133b, and hsa-miR-206, a correlation between tumor and serum microRNA levels was observed.
  • the ratio of muscle-specific miRNA (hsa-miR-1, hsa-miR-133a, hsa-miR-133b and hsa-miR-206) to hsa-miR-16 (muscle Specific miRNA / hsa-miR-16) is expected as a biomarker of body fluid, particularly serum, at the time of diagnosis of rhabdomyosarcoma.
  • rhabdomyosarcoma is detected separately from other childhood tumors such as neuroblastoma (NB), Ewing sarcoma (EWS), and malignant rhabdomyosarcoma (MRT).
  • NB neuroblastoma
  • EWS Ewing sarcoma
  • MRT malignant rhabdomyosarcoma
  • the expression level of the muscle-specific miRNA of the present invention decreases after treatment of rhabdomyosarcoma, it also serves as an index of therapeutic effectiveness (FIGS. 8, 10, and 11).
  • Example 1 Method Cell line, tumor specimen, serum 16 cell lines (Rhabdomyosarcoma 7, Neuroblastoma 4, Ewing sarcoma 3, Malignant rhabdomyosarcoma 2), 21 tumor specimens (Kyoto Medical University Pediatrics) Rhabdomyosarcoma 7, Undifferentiated sarcoma 4, Wilms tumor 2, Neuroblastoma 2, Ewing sarcoma 1, Malignant rhabdomyosarcoma 1, Adrenal carcinoma 1, Retinoblastoma 1, Alveolar soft tissue sarcoma 1, Bone Sarcoma 1), 48 serum specimens (rhabdomyosarcoma 8, neuroblastoma 3, Wilms tumor 2, Ewing sarcoma 2, hepatoblastoma 2, retinoblastoma 2, osteosarcoma 2, anaplastic sarcoma 2, malignant striated muscle -Like tumor 1, alveolar soft tissue sarcoma 1, adrenal carcinoma 1, pancreatoblastoma 1, ter
  • RNA containing miRNA was extracted using mirVana PARIS kit (Ambion). For the supernatant and serum of the cell line culture solution, centrifugation was further performed at 15,000 rpm for 10 minutes to remove cell components, and the supernatant was used.
  • Reverse transcription reaction A reverse transcription reaction was performed using mature miRNA specific reverse transcription reaction primers of Taqman MicroRNA RT kit (Applied Biosystems) and Taqman MicroRNA assays (Applied Biosystems).
  • Quantitative real-time PCR was performed using reverse transcribed cDNA solution, Taman MicroRNA assyas primers and probes. In specimens other than body fluids, expression variation was small between tissues, and the highly expressed hsa-miR-16 was used as an endogenous control, and the expression of muscle-specific miRNA was normalized and quantified using the ⁇ Ct method. Since the expression of hsa-miR-16 was not constant in the body fluid sample, a calibration curve was created using a synthetic miRNA with a known copy number and quantified using absolute quantification. Hsa-miR-206 copy number per 1 ⁇ l of serum was calculated and compared. Table 1 shows the sequences of muscle-specific miRNAs (hsa-miR-1, 133a, 133b, 206) and hsa-miR-16.
  • rhabdomyosarcoma cell line culture supernatant 7
  • neuroblastoma 4
  • Hsa-miR-133a, 133b, and 206 showed a significant correlation (Table 2).
  • Table 2 we examined the changes in the expression of muscle-specific miRNA due to treatment in 3 cases in which paired sera were obtained before and after treatment, and all were below the cut-off value after treatment, and the expression was normal. It decreased to the same level as human volunteers ( Figure 8). Serum muscle-specific miRNAs increased or decreased to reflect the disease of rhabdomyosarcoma, decreased upon successful treatment, and increased upon relapse or exacerbation ( Figure 10).
  • rhabdomyosarcoma is the most common soft tissue sarcoma in children, there is currently no tumor marker that can be measured by blood tests, and its preoperative diagnosis is difficult.
  • this tumor the presence of residual tumor after the first operation is a poor prognostic factor, so if a provisional diagnosis of rhabdomyosarcoma has been made before the first operation, it is possible to plan an operation aiming for total resection. it can. For this reason, the presence of noninvasive biomarkers that lead to preoperative diagnosis of rhabdomyosarcoma is important.
  • the muscle-specific miRNA examined this time is considered to be a novel biomarker that enables preoperative diagnosis of rhabdomyosarcoma with high sensitivity and specificity and can contribute to the improvement of prognosis.
PCT/JP2011/058843 2010-04-08 2011-04-07 体液由来検体を用いた横紋筋肉腫の検出方法 WO2011126089A1 (ja)

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Application Number Priority Date Filing Date Title
JP2012509705A JP5928725B2 (ja) 2010-04-08 2011-04-07 体液由来検体を用いた横紋筋肉腫の検出方法
US13/639,183 US8975021B2 (en) 2010-04-08 2011-04-07 Method for detecting rhabdomyosarcoma using sample derived from body fluid
CA2795430A CA2795430A1 (en) 2010-04-08 2011-04-07 Method for detecting rhabdomyosarcoma using sample derived from body fluid
CN201180028448.9A CN103108953B (zh) 2010-04-08 2011-04-07 使用来自体液的样本检测横纹肌肉瘤的方法
EP11765989.6A EP2557162B1 (en) 2010-04-08 2011-04-07 Method of detecting rhabdomyosarcoma using sample derived from body fluid
ES11765989.6T ES2549452T3 (es) 2010-04-08 2011-04-07 Método de detección de un rabdomiosarcoma que utiliza una muestra derivada de un líquido corporal
KR1020127027613A KR20130069587A (ko) 2010-04-08 2011-04-07 체액 유래 검체를 사용한 횡문근육종의 검출 방법

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JP2010-089180 2010-04-08

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US8975021B2 (en) 2015-03-10
US20130203062A1 (en) 2013-08-08
EP2557162B1 (en) 2015-07-08
CA2795430A1 (en) 2011-10-13
EP2557162A4 (en) 2013-11-06
JPWO2011126089A1 (ja) 2013-07-11
KR20130069587A (ko) 2013-06-26
CN103108953B (zh) 2015-04-08
CN103108953A (zh) 2013-05-15
ES2549452T3 (es) 2015-10-28
JP5928725B2 (ja) 2016-06-01
EP2557162A1 (en) 2013-02-13

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